Renal Failure - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

RENAL FAILURE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Renal Failure: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84606-5 1. Renal Failure-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on renal failure. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 9 CHAPTER 1. STUDIES ON RENAL FAILURE ...................................................................................... 11 Overview...................................................................................................................................... 11 The Combined Health Information Database............................................................................... 11 Federally Funded Research on Renal Failure............................................................................... 25 E-Journals: PubMed Central ....................................................................................................... 82 The National Library of Medicine: PubMed ................................................................................ 85 CHAPTER 2. NUTRITION AND RENAL FAILURE ............................................................................ 133 Overview.................................................................................................................................... 133 Finding Nutrition Studies on Renal Failure.............................................................................. 133 Federal Resources on Nutrition ................................................................................................. 137 Additional Web Resources ......................................................................................................... 138 CHAPTER 3. DISSERTATIONS ON RENAL FAILURE ........................................................................ 141 Overview.................................................................................................................................... 141 Dissertations on Renal Failure .................................................................................................. 141 Keeping Current ........................................................................................................................ 142 CHAPTER 4. CLINICAL TRIALS AND RENAL FAILURE .................................................................. 143 Overview.................................................................................................................................... 143 Recent Trials on Renal Failure .................................................................................................. 143 Keeping Current on Clinical Trials ........................................................................................... 156 CHAPTER 5. PATENTS ON RENAL FAILURE................................................................................... 159 Overview.................................................................................................................................... 159 Patents on Renal Failure............................................................................................................ 159 Patent Applications on Renal Failure ........................................................................................ 179 Keeping Current ........................................................................................................................ 213 CHAPTER 6. BOOKS ON RENAL FAILURE ...................................................................................... 215 Overview.................................................................................................................................... 215 Book Summaries: Federal Agencies............................................................................................ 215 Book Summaries: Online Booksellers......................................................................................... 220 Chapters on Renal Failure.......................................................................................................... 227 CHAPTER 7. MULTIMEDIA ON RENAL FAILURE............................................................................ 245 Overview.................................................................................................................................... 245 Video Recordings ....................................................................................................................... 245 Audio Recordings....................................................................................................................... 246 CHAPTER 8. PERIODICALS AND NEWS ON RENAL FAILURE ........................................................ 249 Overview.................................................................................................................................... 249 News Services and Press Releases.............................................................................................. 249 Newsletters on Renal Failure..................................................................................................... 252 Newsletter Articles .................................................................................................................... 253 Academic Periodicals covering Renal Failure ............................................................................ 256 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 259 Overview.................................................................................................................................... 259 U.S. Pharmacopeia..................................................................................................................... 259 Commercial Databases ............................................................................................................... 263 Researching Orphan Drugs ....................................................................................................... 264 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 269 Overview.................................................................................................................................... 269 NIH Guidelines.......................................................................................................................... 269 NIH Databases........................................................................................................................... 271 Other Commercial Databases..................................................................................................... 273 The Genome Project and Renal Failure...................................................................................... 273

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APPENDIX B. PATIENT RESOURCES ............................................................................................... 277 Overview.................................................................................................................................... 277 Patient Guideline Sources.......................................................................................................... 277 Finding Associations.................................................................................................................. 306 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 309 Overview.................................................................................................................................... 309 Preparation................................................................................................................................. 309 Finding a Local Medical Library................................................................................................ 309 Medical Libraries in the U.S. and Canada ................................................................................. 309 ONLINE GLOSSARIES................................................................................................................ 315 Online Dictionary Directories ................................................................................................... 315 RENAL FAILURE DICTIONARY............................................................................................... 317 INDEX .............................................................................................................................................. 431

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with renal failure is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about renal failure, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to renal failure, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on renal failure. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to renal failure, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on renal failure. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON RENAL FAILURE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on renal failure.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and renal failure, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “renal failure” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Prevention and Treatment of Acute Renal Failure in Sepsis Source: JASN. Journal of the American Society of Nephrology. 14(3): 792-805 March 2003. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Website: www.jasn.org/. Summary: Acute renal failure (ARF) is a common complication of sepsis and has a poor prognosis. Mortality (death) was reported higher in patients with septic ARF (74.5 percent) than in those whose renal (kidney) failure did not result from sepsis (45.2 percent). This article discusses the use of drug therapy to interfere with each of the dysfunctional pathways to improve the course of septic ARF. These include inhibition of inflammatory mediators, improvement of renal hemodynamics (blood flow) by

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amplifying vasodilator mechanisms and blocking vasoconstrictor mechanisms, interruption of leukocyte infiltration, inhibition of the coagulation cascade, and administration of growth factors to accelerate renal recovery. The author also highlights the available supportive measures, including dialysis, that can be used for septic patients with ARF. The author notes that, unfortunately, treatment of ARF in sepsis is still only supportive; there have been no conclusive drug therapies available to treat the condition. 1 figure. 1 table. 136 references. •

Impact of Burn Size and Initial Serum Albumin Level on Acute Renal Failure Occurring in Major Burn Source: American Journal of Nephrology. 23: 55-60. January-February 2003. Contact: Available from S. Karger Publishers, Inc. 26 West Avon Road, P.O. Box 529, Farmington, CT 06085. (800) 828-5479. Website: www.karger.com. Summary: Acute renal (kidney) failure (ARF) is not a rare occurrence in severe burns and is an important complication leading to an increase in mortality (death). The severity of the burn is largely determined by the burn size, and severe burns are likely to cause enough loss of extracellular fluid and albumin from plasma volume to produce shock and hypoalbuminemia (low levels of the protein albumin in the blood). This article reports on a study in which the authors hypothesized that initial serum albumin level may be useful as an indicator of prognosis and severity of injury in burned patients. The authors retrospectively analyzed the clinical characteristics of 147 adult patients with second-and third-degree burns covering 30 percent or more of their body surface area. Of the 147 patients, 27 (19 percent) experienced ARF, defined as a serum creatinine greater than 2 milligrams per deciliter, during the admission. The patients with ARF had larger burn size and lower serum albumin concentration at admission, compared with those without ARF. All patients with ARF expired, whereas 29.4 percent (35 of 119 patients) of the patients without ARF died. The burn size greater than 65 percent was associated with a risk of ARF that was 9.9 times and with a risk of death that was 14.2 times as high as that for burn size less than 65 percent. The authors conclude that when major burns are complicated by ARF, the mortality rate increases significantly. Burn size is an independent predictor of ARF occurring in major burns. Initially depressed serum albumin level is associated with an increase in mortality in the major burn patients. 3 figures. 4 tables. 21 references.

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Slowing the Progression of Chronic Renal Failure: Economic Benefits and Patients' Perspectives Source: American Journal of Kidney Diseases. 39(4): 721-729. April 2002. Contact: Available from W.B. Saunders Company. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: Because of the predicted increase in end stage renal disease (ESRD) incidence, prevalence, and cost, a cohesive national effort is needed to develop strategies to slow the progression of chronic renal (kidney) failure (CRF). The question arises of how much reduction in the progression of CRF would lead to a meaningful decrease in the prevalence and cost of ESRD. This article reports on the development of a mathematical model to assess the economic impact of decreasing the progression of CRF by 10 percent, 20 percent, and 30 percent. United States Renal Data System (USRDS) projections were used to model the rate of increase in ESRD incidence and prevalence. Glomerular filtration rate (GFR, a measure of kidney function) at the initiation of ESRD therapy and cost per patient year were based on USRDS data. The authors also

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determined how much slowing of the progression of CRF is important from patients' perspectives by means of a written questionnaire (which inquired about willingness to go on a restricted diet, take six extra medications per day, and make six extra office visits per year). The authors note that their data suggest that the cumulative economic impact of slowing the progression of CRF, even by as little as 10 percent, would be staggering. The authors call for the development and implementation of intensive renoprotective (protecting the kidney) efforts beginning at the early stages of chronic renal disease and continued throughout its course. 2 figures. 5 tables. 48 references. •

Precision of Estimating Protein Intake of Patients with Chronic Renal Failure Source: Kidney International. 62(5): 1750-1756. November 2002. Contact: Available from Blackwell Science, Inc. Journals Fulfillment Department, 350 Main Street, Malden, MA 02148. (781) 388-8250. Summary: Biochemical methods for estimating protein intake are based on the concept that nitrogen-containing products of protein in diet, plus the products arising from endogenous protein, are excreted as either urea or non-urea nitrogen (NUN). The urea nitrogen appearance (UNA) rate is measured as the amount of urea excreted in urine plus the net amount accumulated in body water. This article reports on a study in which the authors examined nitrogen balance and its components measured in 33 patients with chronic renal (kidney) failure (CRF) who were eating diets varying from 4.1 to 10.1 grams of nitrogen per day. The authors evaluated relationships between dietary nitrogen, NUN, fecal nitrogen, body weight, and the predictability of the two methods of measurement (a standard measure of nitrogen intake versus a recently-proposed measure named for Maroni). The authors conclude that fecal nitrogen is not correlated with nitrogen intake, NUN is not constant but varies with weight, and the traditional method of estimating nitrogen intake in stable chronic renal insufficiency (CRI) patients from UNA and weight as proposed by Maroni et al is valid. 4 figures. 2 tables. 30 references.

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Renal Osteodystrophy in Chronic Renal Failure Source: Seminars in Nephrology. 22(6): 488-493. November 2002. Contact: Available from W.B. Saunders Company. Periodicals Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: Bone disease develops relatively early in the development of chronic renal (kidney) failure (CRF). Renal osteodystrophy is the nonspecific term used to describe the many bone and mineral complications associated with renal disease. This article explores renal osteodystrophy in CRF. The authors note that much of what is known about the evaluation and management of renal osteodystrophy in CRF is based on knowledge obtained in the dialysis population. The classic bone lesion found in the dialysis population is osteitis fibrosa, the high turnover lesion of secondary hyperparathyroidism. Clearly, hypocalcemia (low levels of calcium in the blood), hyperphosphatemia (high levels of phosphate in the blood), and calcitriol deficiency play major roles in the development and maintenance of the high turnover disease. Interestingly, in both the dialysis and nondialysis population, the incidence of adynamic bone disease, a low turnover lesion, is increasing. The authors postulate that the aggressive use of calcium-containing phosphate binders and the use of calcitriol and other vitamin D analogs to treat secondary hyperparathyroidism may contribute to this shift in bone lesions. Treatment in the nondialysis kidney disease patient remains aggressive correction of hypocalcemia and hyperphosphatemia. The use of calcitriol and

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other agents to maintain serum calcium and to suppress elevated parathyroid hormone remains well supported. However, the increase in extraskeletal calcifications and incidence of adynamic bone disease in these patients raises concern about current management techniques. 1 figure. 2 tables. 35 references. •

Renal Failure and Deafness: Branchio-Oto-Renal Syndrome Source: American Journal of Kidney Diseases. 32(2): 334-337. August 1998. Contact: Available from W.B. Saunders Company. P.O. Box 628239, Orlando, FL 328628239. (800) 654-2452. Fax (800) 225-6030. E-mail: [email protected]. Website: www.ajkd.org. Summary: Branchio oto renal (BOR) syndrome is a rare autosomal dominant condition that may present with hearing loss, branchial cysts, and renal failure. The characteristic phenotypic expression of the full syndrome may be partial or complete, and a whole range of renal (kidney) abnormalities may be present. The similarity of BOR to Alport's syndrome may lead to misdiagnosis. This article presents a case report of adult onset renal failure in a 44 year old white man with deafness, previously believed to have Alport's syndrome. The patient's hearing loss was believed to be congenital, and he was prescribed hearing aids. By the age of 19 years, deafness had worsened significantly, and a diagnosis of bilateral moderately severe mixed hearing loss was made. The authors review the relevant literature. The authors note that it is not clear why there is an association between renal malformation and abnormalities of the ear. 2 figures. 18 references.

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Varicella Vaccination in Children with Chronic Renal Failure: A Report of the Southwest Pediatric Nephrology Study Group Source: Pediatric Nephrology 18(1): 33-38. January 2003. Contact: Available from Springer-Verlag. Service Center Secaucus, 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. Summary: Children with kidney disease are at risk for serious varicella related complications. This article reports on a study undertaken to evaluate the safety and immunogenicity of a two-dose regimen of varicella (the virus that causes chickenpox) vaccine in children (aged 1 to 19 years, n = 96) with chronic renal (kidney) insufficiency and on dialysis. Of the 96 patients, 50 (mean age 4.2 years) had no detectable varicella zoster virus (VZV) antibody; 98 percent sero-converted after the two-dose vaccine regimen. At 1, 2, and 3 years' follow up, all patients studied maintained VZV antibody, including 16 who received a transplant. No significant vaccine-associated adverse events were seen. One subject developed mild varicella 16 months post transplant. In multivariate regression analysis, patients vaccinated after 6 years of age had VZV antibody levels 73 percent lower than patients vaccinated before 6 years of age. The authors conclude that a two-dose varicella vaccination regimen was generally well tolerated and highly immunogenic in children with chronic kidney disease. 1 figure. 2 tables. 25 references.

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Hepatitis C and Renal Failure Source: American Journal of Medicine. 107(6B): 90S-94S. December 27, 1999. Contact: Available from Exerpta Medica, Inc. American Journal of Medicine, P.O. Box 7247-7197, Philadelphia, PA 19170-7197. (800) 606-0023 or (609) 786-0841. Fax (609) 7867032.

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Summary: Chronic hepatitis C virus (HCV) infection is common among patients with chronic renal (kidney) failure (CRF). This article reviews the interplay between HCV and kidney failure. The chronic viral infection can result in significant morbidity (illness) and mortality (death). Liver failure from chronic hepatitis C is one of the leading causes of death among long term survivors of kidney transplantation. Between 10 and 20 percent of patients on hemodialysis are chronically infected with HCV. HCV infection also can be a cause of glomerulonephritis (and infection of the kidneys) and nephrotic syndrome (edema, or fluid accumulation, protein in the urine or proteinuria, and susceptibility to infections). The author stresses that primary care physicians need to recognize these conditions in order to optimize the management of patients with CRF. 45 references. •

Influence of Dialysis Membranes on Outcomes in Acute Renal Failure: a MetaAnalysis Source: Kidney International. 62(5): 1819-1823. November 2002. Contact: Available from Blackwell Science, Inc. Journals Fulfillment Department, 350 Main Street, Malden, MA 02148. (781) 388-8250. Summary: Considerable controversy exists as to whether synthetic (more biocompatible) dialysis membranes improve outcome in patients with acute renal (kidney) failure (ARF) compared to cellulose-based membranes. This article reports on a meta-analysis performed on all previously published prospective trials comparing the use of synthetic membranes with cellulose-based membranes for hemodialysis (HD) in patients with ARF. Of the 10 prospective trials identified, 8 trials (867 patients) provided survival data and six trials (641 patients) provided data on recovery of renal function. The authors conclude that synthetic membranes appear to confer a significant survival advantage over cellulose-based membranes. The authors could not demonstrate a similar benefit with use of synthetic membranes over cellulose-based membranes for recovery of renal function, but sample size was limited. The authors note that the survival disadvantage for cellulose-based membranes may be limited to unsubstituted cellulose (cuprophane) membranes. 2 figures. 1 table. 18 references.

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Some Medical Aspects of Nutritional Therapy in Elderly Chronic Renal Failure Patients Source: Dialysis and Transplantation. 31(9): 607-608, 610-614. September 2002. Contact: Available from Dialysis and Transplantation, Attn.: Subscriptions. P.O. Box 10535, Riverton, NJ 08076. (800) 624-4196 or (609) 786-0871. Summary: Elderly chronic renal (kidney) failure (CRF) patients present special problems to the renal team. This article focuses on some medical aspects of nutritional therapy in elderly CRF patients. The authors note that signs due to aging often superimpose on symptoms related to CRF. There are some specific age-associated problems in geriatric patients, such as diminished taste and smell perception, loss of teeth, constipation, poor physical condition, and psychosocial problems including economic limitations, social isolation, and depression. All of these conditions can have a negative impact on the nutritional status in elderly CRF patients. The authors advise a moderate protein restriction and an increased calorie intake in elderly renal patients who are in the Predialysis stage. Metabolic acidosis should be treated to prevent further catabolism, and more intensive nutritional monitoring is advocated to avoid occult (hidden) malnutrition. The authors also discuss the nutritional recommendations for elderly patients on hemodialysis and comment on a new therapeutic trend for the treatment of

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malnutrition in CRF patients, i.e., the use of recombinant forms of human growth hormone and insulin-like growth factor 1. 3 figures. 1 table. 25 references. •

Inflammation and Outcome in End-Stage Renal Failure: Does Female Gender Constitute a Survival Advantage? Source: Kidney International. 62(5): 1791-1798. November 2002. Contact: Available from Blackwell Science, Inc. Journals Fulfillment Department, 350 Main Street, Malden, MA 02148. (781) 388-8250. Summary: Elevated C-reactive protein (CRP) is a strong predictor of cardiovascular events and all-cause mortality (death) in patients with end stage renal disease (ESRD). However, although sex hormones may influence serum levels of inflammatory proteins, gender has not been taken into consideration in previous studies of inflammation and outcome in ESRD patients. This article reports on a study of 663 ESRD patients (374 males) aged 59 years (plus or minus 1 year) from three European renal (kidney) centers (Sweden, Germany, Italy). The relation between outcome and serum levels of the soluble intercellular adhesion molecule (sICAM-1) was evaluated in 312 of the patients. The results show that elevated CRP is a strong predictor of outcome. No difference in allcause mortality was observed between noninflamed males and females. However, inflamed males had a significantly higher mortality rate than inflamed females. The authors conclude that sex hormones may have important cardioprotective effects that limit the effect of inflammation on vascular injury in female ESRD patients. 3 figures. 2 tables. 28 references.

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Hemofiltration and Peritoneal Dialysis in Infection-Associated Acute Renal Failure in Vietnam Source: New England Journal of Medicine. 347(12): 895-902. September 19, 2002. Summary: In some parts of the world, peritoneal dialysis (PD) is widely used for renal replacement therapy (RRT) in acute renal (kidney) failure (ARF). In resource-rich countries, it has been supplanted in recent years by hemodialysis (HD) and, most recently, by hemofiltration and associated techniques. This article reports on an open, randomized comparison study of pumped venovenous hemofiltration and peritoneal dialysis in patients with infection-associated ARF in an infectious disease referral hospital in Vietnam. The study included 70 adult patients with severe falciparum malaria (n = 48) or sepsis (n = 22); 34 were assigned to hemofiltration and 36 to PD. The mortality rate was 47 percent (17 patients) in the group assigned to PD, compared to 15 percent (5 patients) in the group assigned to hemofiltration. The rates of resolution of acidosis and of decline in the serum creatinine concentration in the group assigned to hemofiltration were more than twice those in the group assigned to peritoneal dialysis and RRT was required for a significantly shorter period. The cost of hemofiltration per survivor was less than half that of PD, and the cost per life saved was less than one third. The authors conclude that hemofiltration is superior to peritoneal dialysis in the treatment of infection-associated acute renal failure. 2 figures. 2 tables. 11 references.

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Slowing the Course of Renal Failure in Patients with Diabetes Source: Physician Assistant. 16(10): 79-85. October 1992. Summary: In this article, the authors discuss the incidence and costs involved in diabetes-associated renal disease; the typical course of renal disease in patients with diabetes; the mechanisms of said renal disease; nonpharmacologic intervention; and

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pharmacologic intervention, including the use of diuretics, beta blockers, vasodilators, ACE inhibitors and calcium antagonists, and combination therapy. The authors conclude that aggressive early blood pressure control has been shown to postpone the development of end-stage renal disease significantly and hypothesize that the ACE inhibitors and certain classes of calcium antagonists have the potential to modify the course of diabetic nephropathy even more than traditional antihypertensive therapy. 43 references. •

Impact of Simultaneous Pancreas and Kidney Transplantation on Progression of Coronary Atherosclerosis in Patients with End-Stage Renal Failure due to Type 1 Diabetes Source: Diabetes Care. 25(5): 906-911. May 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Mortality (death) in type 1 diabetes patients with end stage renal failure is high and is dominated by coronary (heart) atherosclerotic events. With regard to prognosis, simultaneous transplantation of pancreas and kidney (SPK) may be superior to kidney transplantation alone (KTA) in these patients, because normalization of blood glucose levels may reduce progression of coronary atherosclerosis and because it is well known that progression of coronary atherosclerosis is one of the major factors that determines clinical prognosis. This article reports on a study that compared progression of coronary atherosclerosis in patients with (n = 26) and those without (n = 6) a functioning pancreas graft after SPK. Mean follow up was 3.9 years. Average glucose control was significantly worse for the patients without a pancreas graft than for patients with a functioning pancreas graft. Regression of atherosclerosis occurred in 38 percent of patients with a functioning pancreas graft compared with 0 percent of patients in whom the pancreas graft was lost. The authors conclude that this observation is an important part of the explanation for the observed improved mortality rates reported in type 1 diabetes patients with end stage renal failure after SPK compared with KTA. In light of these findings, the authors recommend that SPK be carefully considered for all diabetes transplant candidates. 3 figures. 1 table. 40 references.

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Peritoneal Dialysis in Acute Renal Failure: Why the Bad Outcome? (editorial) Source: New England Journal of Medicine. 347(12): 933-935. September 19, 2002. Summary: Mortality rates among patients with acute renal (kidney) failure (ARF) can be quite high, but because this diagnosis encompasses a broad mix of patients, optimal treatment strategies are sometimes not clear. This editorial comments on a research study (published in the same journal issue) that provides evidence of the superiority of venovenous hemofiltration over peritoneal dialysis in patients with ARF. The editorial author considers whether some adverse factor associated with peritoneal dialysis as it was used in this study may also have affected survival. The editorial discusses the equipment and supplies used and the problem of high glucose levels in peritoneal dialysis fluid. The author concludes that, in addition to comparing the ability of peritoneal dialysis, continuous renal replacement therapy, and hemodialysis to remove solute, salt, and water in patients with ARF, it must also be determined whether there are technique-specific factors that affect outcome. 8 references.

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Nutrition in Children with Preterminal Chronic Renal Failure: Myth or Important Therapeutic Aid? Source: Pediatric Nephrology. 17(2): 111-120. February 2002. Contact: Available from Springer-Verlag. Service Center Secaucus, 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. Summary: Nutrition has been believed to be an important therapeutic instrument in children with chronic renal (kidney) failure for improving growth and for slowing down the deterioration of renal function. The therapeutic strategies for both targets may be conflicting, at least in part, since a high caloric intake is needed for optimal growth, whereas a low protein diet, which was believed to protect renal function, places patients at risk of low calorie intake. This review article considers the role of nutrition in children with preterminal chronic renal failure (CRF). Dietary manipulations for optimal growth are mainly effective in infants with CRF. However, growth remains suboptimal even with an energy intake above 80 percent of RDA. Although a low protein diet is able to slow down the rate of deterioration in renal function in rodent studies, the results of prospective clinical studies were disappointing, at least for an observation period up to three years. The conclusions from dracon meta-analyses of these clinical studies in adults are contradictory. The progression rate was not significantly influenced by protein restriction, whereas renal replacement therapy could be postponed. However, the latter seems to be the effect of weakening uremic symptoms during the phase of end stage renal failure. The authors conclude that, according to present knowledge, it is not justified to prescribe special diets to children early in the course of CRF, but the composition of their nutrition should follow the general concept of an optimal mixed diet. 2 figures. 2 tables. 143 references.

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Dialysis, Kidney Transplantation, or Pancreas Transplantation for Patients with Diabetes Mellitus and Renal Failure: A Decision Analysis of Treatment Options Source: Journal of the American Society of Nephrology. 14(2): 500-515. February 2003. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Website: www.jasn.org/. Summary: Patients with type 1 diabetes mellitus and end stage renal (kidney) disease (ESRD) may remain on dialysis or undergo cadaveric kidney transplantation, living kidney transplantation, sequential pancreas-after-living kidney transplantation, or simultaneous pancreas-kidney transplantation. This article reports on a study undertaken to determine the optimal treatment strategy for type 1 diabetes patients with kidney failure. The outcome measures were life expectancy in life-years (LY) and quality-adjusted life expectancy in quality-adjusted life-years (QALY). Living kidney transplantation was associated with 18.30 LY and 10.29 QALY; pancreas after kidney transplantation, 17.21 LY and 10.00 QALY; simultaneous pancreas-kidney transplantation, 15.74 LY and 9.09 QALY; cadaveric kidney transplantation, 11.44 LY and 6.53 QALY; dialysis, 7.82 LY and 4.52 QALY. The results were sensitive to the value of several key variables. Simultaneous pancreas-kidney transplantation had the greatest life expectancy and quality-adjusted life expectancy when living kidney transplantation was excluded from the analysis. The data indicate that living kidney transplantation is associated with the greatest life expectancy and quality-adjusted life expectancy for type 1 diabetes patients with renal failure. Treatment strategies involving pancreas transplantation should be considered for patients with frequent metabolic complications of diabetes. For patients without a living donor, simultaneous pancreas-kidney

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transplantation is associated with the greatest life expectancy. 5 figures. 4 tables. 162 references. •

Effects of Secondary Hyperparathyroidism Treatments on Blood Pressure and Lipid Levels in Chronic Renal Failure Patients Source: Transplantation Proceedings. 34(6): 2041-2043. September 2002. Contact: Available from Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010. (212) 633-3730. Website: www.elsevier.com. Summary: Secondary hyperparathyroidism, a frequent complication in chronic renal (kidney) failure (CRF) patients, is generally managed by controlling hyperphosphatemia, normalizing serum calcium levels, and administering oral or intravenous active vitamin D metabolites. Parathyroidectomy (PTX) is another treatment option when medical therapy fails to control the disease. This article reports on a study undertaken to investigate the effects of medical and surgical therapy on blood pressure and lipid levels in CRF patients. In this study, both medical and surgical therapies resulted in a significant decline in systolic and diastolic blood pressure. The authors conclude that treatment of secondary hyperparathyroidism has beneficial effects not only on renal osteodystrophy (bone disease associated with kidney disease), but also on blood pressure and triglyceride levels. They emphasize the need for surgical treatment of patients who are unresponsive to medical therapy. 4 figures. 13 references.

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Gastrointestinal Complications of Renal Failure Source: Gastroenterology Clinics of North America. 27(4): 875-892. December 1998. Contact: Available from W.B. Saunders. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: Seventy-five percent of patients with end-stage renal disease (ESRD) have gastrointestinal complaints. Although some of these complaints may be specifically related to the techniques and procedures of the dialysis method itself, the physiologic state of chronic uremia is likely to contribute to the development of the majority of symptoms. Uremia is the presence of excessive amounts of urea and other nitrogen waste products in the blood. This article begins with a brief review of the systemic effects of uremic toxins followed by a review of the effects of the uremic state on the esophagus, stomach, duodenum, and pancreas. The effects of ESRD on the gastrointestinal (GI) tract can be divided into complications directly attributable to dialysis and complications that are more systemically related. The majority of complications are likely to be related to the latter. Dialysis related GI complications include peritonitis and sclerosing peritonitis. Esophageal abnormalities associated with the uremic state include esophagitis, motility disorders, and hiatal hernia. Stomach involvement in ESRD can include gastritis and duodenitis (infections), abnormal gastric emptying, peptic ulcer disease, and vascular ectasias (blood vessel distension). Other problems can include amyloidosis, abnormal pancreatic morphology, and pancreatitis. The author concludes that unless the supply of donor kidneys increases dramatically, these complications of ESRD will continue to be an important clinical issue for gastroenterologists, given the large percentage of patients with symptoms. 4 tables. 99 references.

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Acute Renal Failure Mortality in Hospitalized African Americans: Age and Gender Considerations Source: Journal of the National Medical Association. 94(3): 127-134. March 2002. Summary: The aging kidney is at risk for both toxic and hemodynamic induced acute damage, resulting in a high incidence of acute renal (kidney) failure (ARF) in elderly patients. This article reports on a 3 year computer assisted retrospective review in which the effect of age and or gender in ARF mortality in African Americans (AA) was studied. In an inner city medical center, 100 patients classified as ARF at discharge or death were included in the study. Patients were classified into 3 age categories: younger than 40 years, 40 to 64 years, and older than 64 years. The incidence of ARF was 35 percent, 28 percent, and 37 percent, respectively. Patients greater than 64 years of age were less likely to be put on dialysis. Both pre and post renal causes of ARF were more common in patients greater than 64 years of age than in younger patients. Hospital length of stay increased progressively with age. Mortality (rate of death) was lower in patients older than 64 years of age than in younger patients. The incidence of ARF was higher in male than female patients and the incidence of sepsis (generalized infection) was higher in female than male patients. Dialysis need was greater in male patients, but mortality was higher in female than male patients. Analyses showed that in the presence of sepsis, oliguria (decreased ability to form urine) and mechanical ventilatory support, the relative risk of mortality associated with advanced age was 16.5, the relative risk of mortality associated with female gender was 0.2. In summary, hospitalized elderly AA patients have a high incidence of ARF, and patients less than 40 years of age are equally at risk. Although mortality was higher in female patients, gender and advanced age did not independently contribute to high mortality. Neither age nor gender considerations should replace sound clinical judgement in the management of and decision making in elderly African American patients with ARF. 5 figures. 3 tables. 25 references.

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Microvascular Endothelial Injury and Dysfunction During Ischemic Acute Renal Failure Source: Kidney International. 62(5): 1539-1549. November 2002. Contact: Available from Blackwell Science, Inc. Journals Fulfillment Department, 350 Main Street, Malden, MA 02148. (781) 388-8250. Summary: The pathophysiology of ischemic (lack of blood flow) acute renal failure (ARF) appears to involve a complex interplay between renal (kidney) hemodynamics, tubular injury, and inflammatory processes. A growing body of evidence supports the contribution of altered renal vascular function (the blood flow) in potentially starting and subsequently extending the initial tubular injury. In this article, the authors propose that the 'extension phase' of ischemic ARF involves changes in renal perfusion, continued hypoxia (inadequate levels of oxygen), and inflammatory processes that all contribute to continued tubular cell injury. Vascular endothelial (the lining of the blood vessels) cell injury and dysfunction play a vital part in this extension phase. Vascular congestion, edema (fluid accumulation) formation, diminished blood flow, and infiltration of inflammatory cells have been documented in the corticomedullary junction of the kidney, but linking their genesis to vascular endothelial injury and dysfunction have been difficult. The authors explore how new investigative approaches can further the understanding of the pathophysiology of ischemic ARF. This, in turn, should provide new diagnostic and therapeutic approaches to ischemic ARF. 4 figures. 132 references.

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Early Initiation of Dialysis Fails to Prolong Survival in Patients With End-Stage Renal Failure Source: JASN. Journal of the American Society of Nephrology. 13 (8): 2125-2132. August 2002. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Summary: There is a trend to start dialysis earlier in patients with chronic renal (kidney) failure (CRF). Studies that suggest improved survival from earlier initiation are flawed in that they have measured survival from start of dialysis rather than from a time point before dialysis, when patients have the same renal function. This flaw is termed leadtime bias. This article reports on a study that used the electronic patient record at the renal unit of Glasgow Royal Infirmary to identify all patients who had received dialysis for CRF and who had sufficient data to calculate the time point that they reached a certain level of creatinine clearance (a measure of kidney function). This date was used to time survival. Results showed no significant benefit in patient survival from earlier initiation of dialysis. Patients who started dialysis with a lower estimated creatinine clearance tended to survive longer. This relationship retained significance when gender, age, weight, presence of diabetes, mode of first dialysis, initial dialysis access, hemoglobin, serum albumin, blood leukocyte count, Wright Khan index, and estimated creatinine clearance at the start of dialysis were taken into account. The authors conclude that their study fails to support a policy of earlier initiation of dialysis for patients with end stage renal disease (ESRD). 3 figures. 4 tables. 30 references.

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Eight-Year-Old Boy with Recurrent Macroscopic Hematuria, Weight Loss, and Kidney Failure Source: The Journal of Pediatrics. 142(3): 342-345. March 2003. Contact: Mosby, Inc. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: This article describes a case of an 8 year old boy who was examined by the authors in the emergency department; the boy had a third episode of macroscopic hematuria (visible blood in the urine), which had lasted for 6 days. This symptom was accompanied by a dull, bilateral back and paraumbilical abdominal pain of moderate intensity. The color of the urine was dark brown (tea-colored). The authors describe the case in detail and then consider the differential diagnosis. When the boy's clinical course deteriorated and a rapidly progressive renal insufficiency ensued, a definite histologic diagnosis was sought with kidney biopsy. The histopathologic diagnosis was a primary malignant non-Hodgkin lymphoma with a precursor T-cell phenotype. 3 figures. 19 references.

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Hypokalemic Salt-Losing Tubulopathy with Chronic Renal Failure and Sensorineural Deafness Source: Pediatrics. 108(1): [9 p.]. July 2001. Contact: Available from American Academy of Pediatrics. 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (888) 227-1773. Fax (847) 434-8000. E-mail: [email protected]. Website: www.pediatrics.org. Full text of this article is available at www.pediatrics.org/cgi/content/full/108/1/e5.

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Summary: This article describes a rare inherited hypokalemic (low levels of potassium) salt losing tubulopathy (kidney disease) with linkage to chromosome 1p31. The authors conducted a retrospective analysis of the clinical data for 7 patients in whom cosegregation of the disease with chromosome 1p31 had been demonstrated. In addition, in 1 kindred, prenatal diagnosis in the second child was established, allowing a prospective clinical evaluation. Clinical presentation (symptoms) of the patients was similar and included premature birth attributable to polyhydramnios, severe renal (kidney) salt loss, normotensive hyperreninemia, hypokalemic alkalosis, and excessive hyperprostaglandin E urea, which suggested the diagnosis of hyperprostaglandin E syndrome and antenatal Bartter syndrome. However, the response to indomethacin was only poor, accounting for a more severe variant of the disease. The patients invariably developed chronic renal failure. The majority had extreme growth retardation, and motor development was markedly delayed. In addition, all patients turned out to be deaf. The authors conclude that this hypokalemic salt losing tubulopathy with chronic kidney failure and sensorineural deafness represents not only genetically but also clinically a disease entity distinct from hyperprostaglandin E syndrome and antenatal Bartter syndrome. A pleiotropic (causing multiple, seemingly unrelated symptoms) effect of a single gene defect is most likely causative for syndromic hearing loss. 6 figures. 1 table. 41 references. •

Chronic Renal Failure: Slowing the Onset, Changing the Course Source: Patient Care. 33(19): 76, 78, 83-88. November 30, 1999. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: This article provides health professionals with guidelines for detecting and managing chronic renal disease. Patients who have diabetes mellitus or hypertension are at greatest risk for developing end stage renal disease (ESRD). Patients who have diabetes and microalbuminuria are at substantially increased risk for developing overt renal disease and for death from cardiovascular disease. The early markers of kidney disease, urine protein and serum creatinine levels, can provide valuable information about kidney function. Although proteinuria/albuminuria indicates the onset of diabetic nephropathy, it is also an important early independent marker for kidney disease in patients who have essential hypertension and perhaps other nondiabetic renal diseases. The magnitude of protein in the urine appears to predict rate of progression to ESRD. Patients who have persistent protein excretion of 3 grams per day or more seem to progress to ESRD the fastest. The American Diabetes Association suggests that screening for microalbuminuria begin at diagnosis in patients who have type 2 diabetes, at puberty for children who have type 1 diabetes, and 5 years after onset of type 1 diabetes in older patients. Although serum creatinine is one of the best measures of kidney function, minor elevations are often considered insignificant, and a significantly elevated level is frequently overlooked as an important disease marker. Women with creatinine levels greater than 1.2 milligrams (mg) per deciliter (dL) and men with levels greater than 1.4 mg/dL should undergo further evaluation for kidney dysfunction. Other tests for kidney disease include kidney biopsy. Although whether to order a kidney biopsy for diabetic patients is controversial, a reasonable approach is to obtain a biopsy if there is any doubt or clinical findings are not typical for diabetic nephropathy. Strategies for slowing the progression of renal disease in people who have diabetic nephropathy include controlling blood pressure using angiotensin converting enzyme inhibitors. Sodium restriction may be beneficial for all patients who have renal insufficiency and proteinuria. Complications of ESRD include anemia, metabolic

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acidosis, and osteodystrophy. Early assessment by a nephrology specialist is important. 3 figures. 2 tables. 9 references. •

Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure Source: JASN. Journal of the American Society of Nephrology. 14(2): 425-430. February 2003. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Summary: This article reports on a study undertaken to compare the effects on blood pressure (BP) and sympathetic activity of chronic treatment with an ACE inhibitor (enalapril) and an AngII receptor blocker (losartan) in hypertensive patients (n = 10) with chronic renal (kidney) failure (CRF). Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced muscle sympathetic nerve activity (MSNA) and average 24 hour BP. Plasma renin activity (PRA) was not different during the treatments; baroreceptor sensitivity was not affected by the treatment. The authors conclude that in hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients. 3 figures. 1 table. 30 references.

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Effect of Restricting Dietary Protein on the Progression of Renal Failure in Patients with Insulin-Dependent Diabetes Mellitus Source: New England Journal of Medicine. 324(2): 78-84. January 10, 1991. Summary: This article reports on research that studied the effect of reduced intake of protein and phosphorus on the progression of renal disease in 35 patients with insulindependent diabetes mellitus (IDDM) and clinically evident nephropathy. The lowprotein, low-phosphorus diet contained 0.6 g of protein per kilogram of ideal body weight per day, 500 to 1000 mg of phosphorus, and 2000 mg of sodium. The control diet consisted of the patient's prestudy diet with the stipulation that it contain 2000 mg of sodium and at least 1 g of protein per kilogram per day and 1000 mg of phosphorus. Renal function was assessed by measurement of iothalamate and creatinine clearances at intervals of 3 to 6 months, and the patients were followed for a minimum of 12 months. Results demonstrated that dietary restriction of protein and phosphorus can retard the progression of renal failure in patients with IDDM who have nephropathy. 1 figure. 3 tables. 38 references. (AA-M).

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Role of Parenteral Nutrition in Inflammatory Bowel Disease, Acute Renal Failure, and Hepatic Encephalopathy Source: International Journal of Technology Assessment in Health Care. 6(4): 655-662. 1990. Summary: This article reviews the evidence concerning efficacy and safety of the use of parenteral nutritional support (also called total parenteral nutrition or TPN) in three clinical situations: as a primary therapy for patients with inflammatory bowel disease, for patients with acute renal failure, and for patients with hepatic cirrhosis resulting in encephalopathy. For each of the three situations, the rationale, efficacy, safety, and

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recommendations for using TPN are given. The authors conclude that the true value of parenteral nutritional support in these three clinical indications remains unknown. It is possible that future clinical trials will demonstrate the value of parenteral nutrition for these patients or for subgroups of these patients. 32 references. •

Current Issues and Future Perspectives of Chronic Renal Failure Source: JASN. Journal of the American Society of Nephrology. 13 (Supplement 1): S3-S6. January 2002. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Summary: This brief review article discusses some key issues of end stage renal disease (ESRD) and the prevention strategy for chronic progressive renal disease. The authors focus primarily on the issues in Japan and the United States because they represent and illustrate common problems pertaining to ESRD. Although some dialysis patients live longer than 5 to 10 years and are able to work and contribute to the society in which they live, others fare poorly and die within 2 to 3 years of going on dialysis. In addition to mortality (death), another issue surrounding ESRD is a rapidly aging dialysis population, in part related to the fact that the major proportion of new patients entering dialysis programs comprise people with type 2 diabetes. These problems require the worldwide nephrology community to rededicate itself to the retardation and prevention of the progression of all forms of renal disease. The authors discuss kidney transplantation, peritoneal dialysis, the complications of chronic dialysis, control of hypertension (high blood pressure), the role of dietary protein intake, and the potential impact of advances in molecular biology and genetic engineering. 2 tables. 8 references.

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Nutritional Status of Chronic Renal Failure Patients Following the Initiation of Hemodialysis Treatment. (editorial) Source: American Journal of Kidney Diseases. 40(1): 205-207. July 2002. Contact: Available from W.B. Saunders Company. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: This editorial serves as an introduction to two related articles in this journal on the nutritional status of chronic renal failure (CRF) patients following the initiation of hemodialysis treatment. The author notes that the two papers have virtually identical titles and nearly the same conclusion; namely, that the initiation of chronic hemodialysis therapy in incident CRF patients is associated with improvement in nutritional status. The author discusses how these observations are important in a number of areas, including the predialysis management of chronic renal (kidney) insufficiency, when to initiate hemodialysis, subsequent nutritional status of patients on hemodialysis, and the influence of all of these on the long term outcome of patients with chronic renal insufficiency. The author concludes that until further information regarding nutrition, early start, dose and flux is obtained, these current studies certainly give credence to the National Kidney Foundation KDOQI recommendations on the initiation of dialysis therapy on malnourished patients with advanced chronic renal failure in whom other interventions have failed to result in nutritional improvement. 10 references.

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Oral Health in Children with Chronic Renal Failure Source: Pediatric Nephrology 18(1): 39-45. January 2003.

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Contact: Available from Springer-Verlag. Service Center Secaucus, 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. Summary: This study investigated oral health in 70 children (aged 4 to 13.6 years) with chronic renal (kidney) failure (CRF). Indices were recorded for dental caries (cavities), dental plaque, gingival (gum) inflammation, gingival enlargement, and enamel defects. Salivary urea, buffering capacity, and the oral streptococcal flora were determined for 25 of the children. A significantly greater proportion of the CRF children was caries free, 40 percent compared with 8.5 percent of the controls. The mean plaque score was significantly greater in the CF group for both the primary (12.7) and permanent dentition (22.0) compared with the controls: 5.3 and 15.5, respectively. Eight CRF children had gingival enlargement. Enamel defects affecting the permanent teeth were observed in 57 percent of the CRF children compared with 33 percent of the controls. The buffering capacity was significantly greater in the CRF group, pH 6.4 compared with the controls' pH 5.6. The mean salivary urea level was significantly greater in the CRF children. The isolation frequency of Streptococcus mutans was significantly greater from controls compared with the CRF children. The authors conclude that an integrated dental service needs to be developed with emphasis on toothbrushing to prevent gingival hyperplasia and periodontal disease after puberty in this population. 7 tables. 34 references.

Federally Funded Research on Renal Failure The U.S. Government supports a variety of research studies relating to renal failure. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to renal failure. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore renal failure. The following is typical of the type of information found when searching the CRISP database for renal failure: •

Project Title: A PROSPECTIVE STUDY OF CARDIOVASCULAR DISEASE IN ESRD Principal Investigator & Institution: Klag, Michael J.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-MAR-2005 Summary: (taken from the application) We are in the midst of an epidemic of end stage renal disease (ESRD). Treated ESRD has increased exponentially at an annual rate of 8% since 1973 when the U.S. ESRD treatment registry was initiated. Although it preserves

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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life, treated ESRD is associated with poor quality of life, considerable morbidity, and high mortality. The leading cause of death in treated ESRD patients is cardiovascular disease. The Principal Investigator is a leader in the epidemiology and prevention of renal disease who has an outstanding track record in patient-oriented research and mentorship. He has assembled and mentored a team of superb young investigators who are seeking to understand better the reasons for the increased risk of cardiovascular disease in patients with treated ESRD and less severe forms of renal disease. Mentorship is accomplished through a rigorous program of training in epidemiologic methods and intensive involvement in ongoing, federally-funded research projects. Tuition costs are covered by NIH sponsored training grants from NIDDK and NHLBI. The current proposal requests funds to increase the Principal Investigator's ability to mentor trainees and junior faculty by decreasing his substantial administrative commitment. The research projects described in this proposal are built on the foundation of the CHOICE Cohort Study, a national prospective study of over 1,000 incident cases of ESRD. A DNA and serum bank has been established at a central laboratory. Current research project conducted by trainees who will be mentored by the Principal Investigator as part of the current proposal include: 1. The role of emerging risk factors (Lpa, homocysteine, B vitamin, fibrinogen levels) in risk of CVD ESRD patients; 2. Identification of genes that increase risk of progression to ESRD; 3. Risk factors for vascular access failure. This information will lay the groundwork to prevent CVD in ESRD patients by providing the information needed for clinical trials. The Principal Investigator has a long history of successful mentoring in renal disease research. The proposed award will allow him to continue training the next generation of renal disease epidemiologists. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADHERENCE AND ADJUSTMENT IN END-STAGE RENAL DISEASE Principal Investigator & Institution: Christensen, Alan J.; Professor; Psychology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JAN-1995; Project End 31-DEC-2003 Summary: (adapted from investigator's abstract): Increased quality assurance concerns associated with the Medicare End-Stage Renal Disease (ESRD) program underscore the need for research addressing the adaptation and quality of life of ESRD patients. Patients' levels of psychological adjustment and their degree of adherence with ESRD treatment regimen reflect two important criteria that are examined in the present continuation proposal. One central objective of the research involves identifying psychological characteristics that influence medical regimen adherence and emotional adjustment among patients treated with renal dialysis. This will be accomplished using a longitudinal study design that considers the effects of patient individual differences (i.e., coping style) and contextual differences among the available dialysis treatment modalities. A key aspect of the study involves the assessment of patients at an early stage of progressive renal insufficiency, before renal dialysis is clinically necessary. We hypothesize that adherence and adjustment will vary as a joint function of the type of dialysis prescribed and patient individual differences assessed at baseline. For example, we predict that patients' possessing a more active or vigilant style of coping will exhibit more favorable adherence when undergoing a self-administered dialysis treatment modality (e.g., continuous ambulatory peritoneal dialysis) but poorer adherence when receiving staff administered dialysis (e.g., center hemodialysis). A second objective involves identifying patient characteristics that are related to adherence to adjustment among renal transplantation patients. Initial psychosocial assessment will be conducted during the pre-transplant evaluation process. A set of hypotheses regarding

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psychological predictors of patient adherence and changes in emotional well being after transplantation will be tested in a prospective manner. For Example, we hypothesize that patients with a more active style of coping with health-related stress will exhibit better regimen adherence and better emotional adjustment than other transplant patients. We believe the proposed research will extend the role of psychological theory and practice in contributing to the care of ESRD patients. The knowledge generated will add to a growing body of literature that suggests psychosocial assessment information can be useful in the selection f the most beneficial renal treatment modality for a particular patient. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALGESIC USE AND THE RISK OF CHRONIC RENAL FAILURE Principal Investigator & Institution: Curhan, Gary C.; Associate Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-AUG-1998; Project End 31-JUL-2004 Summary: Analgesic-associated nephropathy is potentially fatal and costly yet completely preventable as a cause of renal dysfunction. Retrospective studies have reported an increased risk of renal dysfunction associated with consumption of large amounts of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) but not aspirin. Since these analgesics are widely available and used, their association with renal dysfunction is particularly important. The primary objective of this study is to examine, prospectively, the association between chronic consumption of acetaminophen, aspirin and NSAIDs, and the risk of chronic renal dysfunction, defined as an increase in serum creatinine or a decrease in calculated creatinine clearance during the 5-year study period. From participants in two large female cohorts, the Nurses' Health Studies I and II (NHSI, NHSII), 3 groups of women will be identified, each comprised of 1150 participants (half from each cohort), who reported frequent use of acetaminophen, aspirin, or NSAIDs, and a fourth group of 1150 women who reported no use of these analgesics. Detailed information on dosage and duration of analgesic use will be obtained through supplementary questionnaires, to be mailed in the 01, 03, and 05 years, which have been shown to be reproducible. 4600 nurses will be enrolled at the outset and, after excluding women with prevalent renal disease and those who drop out, an expected 4000 will complete the study in the 05 year. The outcomes are: change in serum creatinine and calculated creatine clearance, measured at baseline and years 03 and 05 from all subjects. Mixed effects regression will be used to analyze the slope of renal function in the unexposed and exposed groups during the 5 year study period. For approximately 2000 subjects in NHSI, stored blood from 1989 will be used to perform the same analyses over a 13 year period. This study will provide: prospective data on change in renal function associated with chronic analgesic use; threshold levels of safe cumulative dose and duration of these analgesics; and population-based incidence rates and attributable risks of analgesic-associated chronic renal dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ASSESSING FUNCTIONAL OUTCOMES IN ADOLESCENT WITH ESRD Principal Investigator & Institution: Furth, Susan L.; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAR-2004

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Summary: provided by applicant): Dr. Furth is seeking the Small Grant Award to expand the study of clinical outcomes for children with end stage renal disease (ESRD) initiated under her KO8 Award DK 02586-01A1. With the support of the KO8 funding, Dr. Furth has completed her PhD in Clinical Investigation and has begun the transition to an independent research career. She has published a number of manuscripts using her training in epidemiology and clinical investigation: examining how clinical and socio-economic factors affect access to different treatment regimens for children with kidney failure, and how clinical experience with ESRD care for children affects treatment decisions. She has examined how poor growth, a crucial pediatric issue, affects mortality, hospitalization rates and educational achievement. She has also initiated a multi-center, cross-sectional study comparing functional outcomes/ health related quality of life (HRQL) for pediatric patients with chronic renal failure or ESRD treated with hemodialysis, peritoneal dialysis or transplant. Resources provided by the RO3 award will allow Dr. Furth to expand the multi-center study of health related quality of life in adolescents with ESRD to a prospective study. A prospective study will allow Dr. Furth to determine whether specific measures of health related quality of life are sensitive to clinical changes, as patients proceed from dialysis to transplantation. The supplementary funding of the R03, additionally will allow Dr. Furth to examine the link between clinical measures such as hematocrit, serum albumin, and dialysis adequacy (Kt/V) and functional outcome/HRQL. Furthermore, the prospective study will assess whether high risk behavior characterized by patterns of response on an adolescent health status questionnaire can predict non-compliance with therapy, increased hospitalization rates, acute rejection or transplant failure. The measures of functional outcome studied will include the Child Health and Illness Profile-Adolescent Edition, and the Child Health Questionnaire (Parent report). This research will provide an indepth analysis of a measure of functional outcome in children with ESRD, and will provide valuable information regarding optimal treatment choices for children with kidney disease. If assessments of high risk behavior predict increased rates of hospitalization, rejection or transplant failure, results of this study will allow identification of a high risk population of adolescents with ESRD, who can be targeted for early intervention and close follow-up to improve long term outcomes of care. The proposal addresses several priority areas for Clinical Research highlighted in the NIH Task Force publication, Research Needs in Pediatric Kidney Disease: 2000 and beyond. During this project, Dr. Furth will gain new skills in organizing and coordinating a prospective multi-center clinical research study. This experience will give Dr. Furth the tools she needs to develop into an independent clinical investigator in a nurturing academic environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BOLD MRI--APPLICATION TO INTRA-RENAL OXYGENATION Principal Investigator & Institution: Prasad, Pottumarthi V.; Evanston Northwestern Healthcare Evanston, Il 60201 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-JAN-2003 Summary: Acute renal failure (ARF) is a syndrome that can be broadly defined as rapid deterioration of renal function resulting in the accumulation of nitrogenous wastes such as urea and creatinine. It is a major clinical problem and is a common hospital acquired syndrome with high mortality rates (approximately 50 percent). The pathophysiology of ischemic acute renal failure, the most common form of clinical ARF, is complex and not yet well understood. Based on previous studies on animal models, it is known that acute renal failure involves damage to the medulla which even under normal circumstances

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must function in an hypoxic environment. Hence an understanding of mechanisms that influence medullary hypoxia is important in the study of pathophysiology of ARF. To date, measurements of intrarenal oxygen tension have been made only with oxygensensitive microelectrodes implanted into the renal parenchyma of animals, a delicate and tedious procedure and impractical for human studies. BOLD (Blood Oxygenation Level Dependent) MRI has shown potential as a noninvasive method to assess on a regional basis the changes in the balance of oxygen supply and demand. We have previously demonstrated a strong correspondence between BOLD MRI measurements in vivo in human kidneys and earlier animal data using invasive microelectrodes. These studies provided evidence for the first time indicating a substantial degree of hypoxia in the human renal medulla. In this proposal, we will further evaluate this technique by comparing the BOLD MRI data obtained in an animal model with oxygenation measurements previously obtained with an invasive microelectrode technique. We will then apply the technique to both animal models and human subjects to derive new information about renal physiology/ pathophysiology especially related to ARF. The availability of a noninvasive method to evaluate regional oxygenation in kidneys in vivo should help to characterize therapeutic and protective mechanisms and thus lead to improved therapeutic and preventive measures for acute renal failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CA2+ HYPERPARATHYROIDISM

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Principal Investigator & Institution: Brown, Alex J.; Associate Professor; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2003 Summary: Parathyroid glands (PTGs) express a calcium-sensing receptor (CaR) that detects the concentration of extracellular calcium and signals the glands to secrete the proper amount of parathyroid hormone (PTH) to maintain normal calcium levels. The calcium-PTH relationship is sigmoidal and can be defined by four parameters: maximum PTH, minimum PTH, the midpoint of the curve (set-point), and the slope at the midpoint. The CaR levels are decreased in the hyperplastic PTGs of patients with secondary HPT (2oHPT) due to chronic renal failure (CRF), but the factors responsible are not known. The impact of this down-regulation on calcium sensitivity remains controversial. In vitro studies indicate decreased calcium sensitivity (elevated set-point) in parathyroid cells from CRF patients, but in vivo assessment of the set-point in CRF patients have yielded mixed results. Furthermore, in patients it is not possible to relate CaR levels to the four parameters of the calcium-PTH relationship. We have now observed a similar reduced CaR expression in hyperplastic PTGs of CRF rats. This model can be used to determine the role of decreased CaR in PTG hyperplasia and the abnormal calcium-PTH relationship, and to identify the factors that regulate the CaR. Definitive identification of the factors that directly control CaR levels requires an in vitro model with stable expression of the CaR. Traditional monolayer cultures do not respond to calcium. We have developed a unique parathyroid cell culture system that preserves the normal cellular architecture, allowing stable CaR expression and calcium response for several weeks. These cultures, which we refer to as pseudoglands or psGs, provide the best available model for studying the regulation off parathyroid cell CaR expression and provide a unique in vitro model t9o examine the effects in CaR levels on the calcium-PTH relationship. This grant presents an experimental approach that utilizes these in vivo and in vitro models to examine both the causes and effects of the downregulation of the CaR in renal failure. The specific aims are: 1. To define the

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relationships, temporal and spatial, between parathyroid gland hyperplasia and downregulation of the CaR in vivo. 2. To examine the effects of established therapies for uremic secondary hyperparathyroidism (phosphate restriction and vitamin D compounds) on CaR expression in uremic rats. 3. To determine the direct effects of potential regulators of CaR expression in vitro using the psG model. 4. To determine the effects of down-regulation of CaR on the calcium- PTH relationship and PTH expression in vivo and in vitro. These studies will provide new information about the effect of decreased CaR in CRF on the calcium-PTH relationship, define the factors responsible for the decrease, and test therapeutic strategies to correct the abnormality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALCINEURIN IN CONGENITAL NEPHROPATHY Principal Investigator & Institution: Chen, Feng; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Congenital obstructive nephropathy is the most frequent cause of renal failure in infants and children. The molecular and cellular lesions leading to the congenital obstruction, however, are still largely undetermined. We hypothesize that calcineurin, a serine/threonine phosphatase, is indispensable for the normal development of the excretory system. We have generated a mouse strain with deletion of the CnB gene in a subset of Pax3 positive cells and their derivatives by Cre-mediated LoxP recombination. These mice have deletion of CnB in the excretory system, including the smooth muscle cells in the ureter. The affected mice have hydronephrosis and hydroureter and die from postnatal renal failure. We plan to further determine the nature, the spectrum, as well as the prenatal and postnatal progression of the congenital nephropathy in the mutants. Of particular interests, our previous experiments have demonstrated an indispensable role of calcineurin in the formation of the vascular smooth muscle layer around the major blood vessels. Based on this finding and our preliminary results, we further hypothesize that the disruption of calcineurin function in the ureteral smooth muscle or in the innervating nerves causes a defective peristalsis, leading to the obstructive nephropathy. To test this hypothesis, we will determine whether the mutants have anatomical or functional defects preventing effective peristalsis and will identify the causative cellular lesions. Finally, we will study the ontogeny of the urinary tract smooth muscle cells and the potential neuronal contribution to the congenital nephropathy. The Pax3Cre-CnB mutants we generated have defined genetic modifications and a consistent early onset congenital obstructive nephropathy leading to kidney failure. These mice will serve as a good animal model to study the causes of congenital obstructive nephropathy. Results from the proposed study will also enhance our understanding of the pyeloureteral peristalsis, the ontogeny of ureteral smooth muscle cells, and the role of calcineurin signaling in these processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARBOHYDRATE AND PROTEIN METABOLIC PATHWAYS Principal Investigator & Institution: Landau, Bernard R.; Professor of Medicine and Biochemistry; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-MAY-1978; Project End 31-MAR-2005 Summary: (Provided by applicant): Carbohydrate, protein and lipid abnormalities characterize diabetes mellitus. Long-term objectives are to develop and apply novel

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methods significantly advancing understanding of those metabolic processes and their regulation in physiological and pathological states in human, and particularly in diabetes. Advantage is taken of 2H2O use to quantitate the pathways followed. Methods have been introduced for carbohydrate and lipid. The major new goal is to develop and apply a method for quantitating protein metabolism. The method for quantitating carbohydrate metabolism will also be further extended. Focus then is on 1) the quantitation of protein synthesis and proteolysis; 2) the contribution to glucose production of gluconeogenesis whose increase in diabetes has been related to the degree of hyperglycemia and 3) the extent of simultaneous hepatic glycogen synthesis and breakdown, called glycogen cycling, which could help explain decreased liver glycogen content found in type 2 diabetes and exacerbate hyperglycemia on glucose ingestion. There are 4 specific aims: 1) To develop and apply a method for quantitating the extent transaldolase reactions contribute to estimates of gluconeogenesis; 2) To evaluate the validity of a method using glucose isotopomers, introduced as a simple method to measure the contribution of gluconeogenesis, in comparison with 2H2O use; 3) To develop a method for quantitating glycogen cycling in the fed state by measuring, along with the rate of hepatic glycogen deposition on glucose intake, how much of the glycogen is formed directly from the glucose, how much from three carbon compounds, and how much from glycogen that is reconverted to glycogen, i.e. glycogen cycling; 4) To develop a method to estimate protein synthesis from labeling of protein by 2H2O, and proteolysis from loss of that label. Initial application of this method will be to renal failure patients undergoing hemodialysis, in whom ingested 2H2O can be removed by dialysis to readily follow loss of incorporated label without continued synthesis of labeled protein. Application first to the renal failure state is done with recognition that nephropathy is a major complication in the diabetic and the potential benefit of a simple method for evaluating the effects of the therapeutic approaches on protein dynamics in that condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIAC OSTEODYSTROPHY

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Principal Investigator & Institution: Kestenbaum, Bryan R.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant):Cardiovascular disease (CVD) accounts for nearly half the mortality, and extensive morbidity, among patients with renal failure. Comorbid illness and traditional cardiac risk factors do not fully explain the epidemic proportion of CVD observed among dialysis patients. Secondary hyperparathyroidism (SHPTH) is a disorder of calcium metabolism found in renal failure that has been linked to cardiovascular (CV) pathology in experimental models of disease. Clinical evidence relating SHPTH with CV outcomes is limited.The three major aims of the proposed study are 1) to estimate the relationship between serum markers of SHPTH and clinical CV outcomes among patients with renal disease, 2) to estimate the relationship between medications regimens used to treat SHPTH and cardiovascular outcomes, and 3) to recruit a new cohort of dialysis patients to participate in pilot studies and serve as a foundation for future research into the relationship between SHPTH and clinical CVD. Two parallel activities will be conducted to address out scientific aims. First, we will study an established cohort of dialysis patients from the United States Renal Database System (USRDS) and an established cohort of chronic renal insufficiency (CRI) patients from the Veterans' Administrations' Consumer Health Information and Performance

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Sets (CHIPS) database. The serum markers of interest are intact PTH, calcium, and phosphate. Medication exposures of interest are dosages of phosphate binders and calcitriol. Second, we will recruit a new cohort of 100 dialysis patients from the Northwest Kidney Center and the Veterans' Administration Medical Center dialysis centers.We will ascertain traditional and novel serum markers of SHPTH among our patient cohorts, and then follow them for the development of subsequent CV related hospitalizations. The primary outcome is time to first cardiovascular hospitalization or cardiovascular death. The proposed study aims to shed light on the relationship between a common renal related metabolic disorder and the epidemic burden of CVD found among this patient population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR CALCIUM TRANSPORT IN URINARY EPITHELIA Principal Investigator & Institution: Friedman, Peter A.; Professor; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-MAR-2003 Summary: The long-term objective of our work is directed toward a complete understanding of the cellular mechanisms and regulation of calcium transport by renal tubular epithelial cells. Although most calcium absorption proceeds in proximal tubules, distal tubules are the site of the physiological regulation of calcium transport by parathyroid hormone (PTH), calcitonin and vitamin D3. The specific aims of the present proposal are to: 1) characterize the mechanism of calcium entry across apical plasma membranes of distal convoluted tubule (DCT) cells; 2) evaluate the participation and regulation of Na+/Ca2+ exchange in mediating calcium efflux; and, 3) define the signaling pathways activated by PTH and calcitonin in DCT cells, and to examine the coordinate regulation of PTH-dependent calcium transport by 1,25(OH)2 vitamin D3 and estradiol. We identified and partially characterized a novel calcium channel that mediates calcium entry. To acquire additional information about these channels we will: 1) characterize the properties of these channels with regard to their ion selectivity, pharmacologic sensitivity and voltage- dependence; 2) determine the regulation of these calcium channels by protein kinases; 3) define the participation of G-proteins in regulating calcium entry channels; and, 4) identify and clone calcium channel transcripts. Extrusion of calcium across basolateral plasma membranes of distal tubules is mediated by Na+/Ca2+ exchange and by /ca2+-ATPase. Pilot studies suggest that Na+/Ca2+ exchange is the dominant efflux mechanism in DCT cells. We will: 1) Test the hypothesis that thiazide diuretics can inhibit Na+/Ca2+ exchange; and 2) Characterize the stimulatory effects of PTH on Na+/Ca2+ exchange. Calcium transport in distal nephrons is regulated by PTH, calcitonin and 1,25(OH)2 vitamin D3. The following studies will evaluate the mechanism mediating the hormonal regulation of calcium transport in DCT cells. The goals of these experiments are to: 1) Characterize the signaling pathways with particular regard to the phospholipases responsible for activating PKA and PKC and characterize the temporal sequence in which PKA and PKC are activated. We will test the hypothesis that PTH and calcitonin activate PKC via phospholipase D. 2) Identify the mechanism by which PTH activates C1- channels, a primary event in membrane hyperpolarization and stimulation of calcium transport in DCT cells. We will test the hypothesis that these chloride channels are regulated by the PKA limb of the PTH-activated signaling pathway. 3) Examine the regulation of vitamin D3 and estradiol accelerate PTH dependent calcium transport by up-regulating PTH receptor expression. The specific aims will be achieved by applying single cell fluorescence, patch clamp, tracer flux measurements, biochemical and molecular

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techniques to a DCT cell line that we developed, which expresses an appropriate phenotype. In selected studies, primary cell cultures of proximal or distal tubule cells will be used to verify results in transformed cells or as controls. All procedures are established in our lab. Results from the proposed experiments will provide new information on the mechanism and regulation of calcium transport in the kidney under normal conditions, but also in calcium-wasting syndromes including hyperparathyroidism, renal failure, osteoporosis and malignancy- associated hypercalcemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONAL SELECTION IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Lenz, Oliver; Medicine; University of MiamiMedical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The prevalence of diabetic nephropathy,the leading cause of end-stage renal failure, has been rising over the past years; despite recent advances in the management of diabetic patients.We have previously shown that the susceptibility to develop progressive glomerulosclerosis varies between mouse strains as it does between different ethnic groups. We identified both sclerosis-prone (ROP) and sclerosis-resistant (C57BL/6) mouse strains, and found that mesangial cells from these strains respond differently to glucose. Our preliminary data show that different subpopulations exist among mesangial cells isolated from sclerosis prone mice. They are characterized by a different length in the d(CA) repeat in the MMP-9 promoter, which recently has been linked to the risk of developing diabetic nephropathy. Rather than using this dinucleotide repeat for linkage studies, we propose that it can be used as a marker for mesangial cell sub-populations. In ROP mesangial cells, we identified single cell clones with d(CA)20 and d(CA)24 repeats. After exposure to high glucose levels, all mesangial cells isolated from ROP mice contained the d(CA)24 dinucleotide repeat. No heterogeneity in the d(CA) dinucleotide repeat length was detected at baseline in mesangial cells isolated from sclerosis-resistant C57BL/6 mice, and no change was observed after exposure to high glucose levels. This led us to propose that in susceptible individuals, diabetes mellitus leads to the clonal expansion of one of the mesangial subpopulations responsible for progressive glomerulosclerosis, and that the length of the d(CA) repeat in the MMP-9 promoter is a suitable marker to distinguish the different sub-populations. We will test the hypothesis that exposure to high glucose levels leads to a clonal selection in mesangial cells cultured from sclerosis-prone ROP mice. We will analyze the differences in gene expression that characterize sub-populations of mesangial cells in low and high glucose levels. The long-term goal of our proposal is to characterize the role of clonal selection in glomerular disease, and identify new targets for screening, prevention, and intervention in the pathogenesis of diabetic nephropathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYTOKINE GENE POLYMORPHISMS IN ACUTE RENAL FAILURE Principal Investigator & Institution: Jaber, Bertrand L.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Acute renal failure (ARF) is a serious complication in hospitalized patients, with an incidence of 5-10%, and mortality exceeding 50% among those who require dialysis. Pro- and anti-inflammatory cytokines play a pivotal

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role in the host inflammatory responses that mediate the severity of ARF. Yet, the importance of susceptibility genetic factors such as cytokine gene polymorphisms has remained largely unexplored. The principal investigator (PI) has designed a rigorous training program that will provide him with the necessary skills, experience, and opportunities to develop into an independent investigator in the field of inflammatory genetic markers and epidemiology of acute renal failure. He will obtain a Masters of Science in Clinical Care Research, participate in projects utilizing a broad range of study designs for clinical research, and carry out an original research project from its inception to completion. His mentors have extensive experience in clinical and laboratory investigation of ARF and clinical care research in Nephrology. Single nucleotide polymorphisms (SNP) in the promoter region of the human tumor necrosis factor-alpha (TNF-alpha) (position -308), interleukin-6 (IL-6) (position -174) and interleukin-10 (IL-10) (position -1082) genes affect transcriptional activity and have functional relevance. These genetically determined differences might influence variations in host inflammatory responses to stressful stimuli. The hypotheses to be investigated are that SNP involving these cytokines predetermine the severity of ARF, and are independent risk factors for adverse clinical outcomes. The specific aims are to: 1) characterize the frequency of these pro- (TNF-alpha and IL-6) and anti-inflammatory (IL-10) cytokine gene polymorphisms in a cohort of patients with ARF; 2) Examine their relationship to leukocyte production and plasma levels of cytokines as well as clinical and laboratory variables; and 3) Evaluate whether these genetic markers individually or in combinations, predict adverse clinical outcomes, mainly dialysis requirement and mortality. The research project is achievable and promises to provide new insights into the importance of genetic markers as novel susceptibility factors for severity of disease in ARF. The results may help identify target patients who may benefit from anti-cytokine therapies. The PI has assembled a team of scientists to assist in the conduct of the project, and convened and internal and external scientific advisory committee to monitor his progress. The proposed training program and research project will prepare him for a career as an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETIC NEPHROPATHY Principal Investigator & Institution: Mauer, Michael S.; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: These continuation studies focus on large pancreas (PTx) and kidney (KTx) transplant populations of type 1 diabetic (D) patients (pts) in order to better understand diabetic nephropathy (DN), the leading cause of renal failure. Objectives are: (a) to determine whether PTx can more readily arrest or reverse the early vs. the more established lesions of DN; (b) to continue studies of renal structural-functional relationships in DN, with emphasis on the multifaceted pathologic DN lesions, including glomerular, vascular, interstitial lesions and glomerular-tubular connections; (c) to continue studies of DN natural history and the role of renal biopsy in predicting outcome; (d) to quantitate and understand the basis of atubular glomeruli (AG) in DN; (e) to elucidate glomerular (glom) epithelial cell abnormalities in DN; (f) to study the glom extracellular matrix abnormalities of DN; (g) to study the recurrence of DN in the KTx; (h) to study the molecular/genetic basis of DN and develop cellular markers of DN risk; (i) to determine the long-term (10-15 yr) structural consequences of cyclosporine (CSA) on the 'native kidneys of PTx recipients; and (j) to determine the shorter-term (5 yr) consequences of Prograf on the native kidneys of PTx recipients and compare these

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with those seen after 5 years of CSA treatment. Together, these studies will help to elucidate the pathogenesis and natural history of DN, unravel some of the molecular and genetic aspects of this disease, describe the dynamics of DN reversal in PTx pts, and recurrence in KTx pts and expand our knowledge of the nephrotoxic effects of calcinosis inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIPYRIDAMOLE IN VASCULAR ACCESS FOR HEMODIALYSIS Principal Investigator & Institution: Himmelfarb, Jonathan; Professor; Maine Medical Center 22 Bramhall St Portland, Me 04102 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: The long-term objective of this proposal is to establish whether or not the use of dipyridamole is efficacious in improving the function of expanded polytetrafluoroethylene (ePTFE) grafts used for dialysis access in patients with end stage renal disease on chronic hemodialysis therapy. Currently, there are over 170,000 patients in the US on chronic hemodialysis therapy. For these patients, problems with vascular access patency have been called the "Achilles Heel" of the dialysis procedure. Furthermore, the development of ePTFE graft stenosis and thrombosis reduces the quality of delivered dialysis therapy and increases the infection risk for patients on dialysis. Maintaining vascular access patency costs approximately $7,871 per hemodialysis patient per year at risk with an estimated annual global cost of more than one billion dollars. Recent evidence suggests that in almost all cases, ePTFE graft thrombosis occurs only after the development of a stenosis either at the graft vein anastomosis or more distally in the vein. These venous stenoses occur because of a pathological process known as intimal hyperplasia. Recent evidence from a small, single-center, prospective, randomized, placebo-controlled clinical trial has suggested that dipyridamole may reduce the rate of ePTFE graft thrombosis in chronic hemodialysis patients. The mechanism of dipyridamole efficacy may be by inhibiting vascular smooth muscle cell proliferation and thereby reducing the development of intimal hyperplasia and associated venous stenoses. The specific aims of this proposal are: l) To investigate the efficacy of dipyridamole in preventing the development of anastomotic and venous stenoses in patients on chronic hemodialysis with ePTFE grafts; and 2) To investigate the efficacy of dipyridamole in preventing the development of thrombosis in patients on chronic hemodialysis with new ePTFE grafts. In order to answer the Specific Aims, the proposed study design is a randomized, prospective, double-blind, placebo-controlled, parallel group clinical trial. Patients on chronic hemodialysis therapy who require a new prosthetic ePTFE graft will be randomized to receive either dipyridamole or placebo for a period of 12 months after enrollment or until ePTFE graft failure. Enrolled patients will undergo serial monitoring of vascular access blood flow, known to be a physiologic predictor of impending vascular access failure, with clinically indicated interventions to prevent vascular access failure. The study design will test the null hypothesis that dipyridamole does not affect the development of either venous stenosis or thrombosis in new ePTFE grafts in hemodialysis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF CLOPIDOGREL ON EARLY PATENCY OF AV FISTULAE Principal Investigator & Institution: Dember, Laura M.; Associate Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118

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Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: Purpose: The objective of this proposal is to design randomized, controlled rnulticenter trials evaluating interventions to increase the survival of vascular access for hemodialysis and to form a collaborative network of clinical centers and a data coordinating center to perform such studies. Specific Aims: This application has two specific research aims: l) To determine whether the administration of clopidogrel for four weeks beginning on the day prior to native fistula creation reduces the rate of early fistula failure compared with placebo, and 2) To create a Collaborative Boston Area Clinical Center with the patient population and clinical and research expertise necessary to conduct the series of studies of the Hemodialysis Vascular Access Clinical Trials Consortium. Background: Maintenance of vascular access for hemodialysis is one of the major challenges in the care of the hemodialysis patient. Access-related problems are among the most frequent reasons for hospitalization in the end-stage renal disease (ESRD) population, and the cost of vascular access placement and repair in the United States currently exceeds $700 million per year. Despite the well-established advantages of native arteriovenous fistulae (higher unassisted potency rates and lower rates of infection) compared to grafts or catheters, the proportion of the United States hemodialysis population with a native fistula is low. An important factor contributing to this low prevalence is early thrombosis of newly created fistulae. Several small studies of antiplatelet agents have shown a reduction in early thrombosis rates of native fistulae, but have not been powered sufficiently to definitively demonstrate a benefit. Methods: Patients with chronic renal failure who are scheduled to undergo creation of a native fistula and are without contraindication to antiplatelet therapy will be randomized to receive either placebo or clopidogrel 75 mg daily beginning the day prior to fistula creation and continuing for an additional 4 weeks. The primary outcome measure will be attainment of a fistula suitable for dialysis without any radiologic or surgical intervention. The secondary outcome measures will be: l) fistula potency at completion of study drug, and 2) attainment of a fistula suitable for dialysis including those fistulae modified radiologically or surgically. The Boston Area Clinical Center will be comprised of five facilities with greater than 600 patients currently on hemodialysis and large preESRD populations from which to draw study subjects. These study sites have extensive successful experience in multicenter clinical trials in ESRD. The Boston Area Clinical Center is organized to efficiently collaborate on the series of clinical trials conducted by the Hemodialysis Vascular Access Clinical Trials Consortium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF SHIGATOXIN-1 ON BRAIN ENDOTHELIAL CELLS Principal Investigator & Institution: Kohan, Donald E.; Chief, Division of Nephrology; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: (adapted from the application) HUS is the leading cause of acute renal failure in children and is characterized by renal injury, microangiopathic hemolytic anemia, and thrombocytopenia. Although the kidney is an initial target in HUS, those patients who die from the disease do so primarily from brain, not renal, involvement. There is, however, very little understanding of how the central nervous system is affected in this disorder. HUS is associated with enteric infection by Shiga toxin (Stx) producing E. coli. The toxin binds to cells expressing a specific glycosphingolipid cell surface Stx receptor (Gb3) whereupon it may exert a variety of effects, including inhibition of protein synthesis, induction of apoptosis, regulation of vasoactive factor production, and others. Generally, these studies have focused on cells thought to be

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primary targets in HUS, namely, renal cells. Very little work, however, has been done on how Stx affects the brain. Preliminary studies from our laboratory indicate that human brain microvascular endothelial cells (HBEC) might be targets of Stx action. Further, these studies suggest that HBEC may respond to Stx and factors likely to be present in the setting of HUS in highly unique manner. Based on these findings, the following hypothesis has been formulated: Unlike renal endothelial cells, HBEC are not normally sensitive to Stx. Soluble or cell-associated members of the inflammatory cytokine superfamily, derived from circulating white blood cells or endothelial cells themselves, cause massive upregulation of Stx responsiveness in HBEC. Such upregulation leads to enhanced white blood cell and possibly platelet adhesion, endothelial cell apoptosis and necrosis, and altered vasoactive factor production. The unique responsiveness of HBEC to cytokine upregulation of Stx-1 sensitivity may provide the basis for therapeutic interventions aimed at blocking cytokine actions on the brain. Accordingly, the specific aims are: 1) Determination of HBEC sensitivity to the cytotoxic and protein synthesis inhibitory effects of Stx-1; 2) Determination of inflammatory factor regulation of the cytotoxic effect of Stx-I in HBEC; 3) Determination of the source(s) of inflammatory cytokines that affect HBEC responsiveness to Stx-1, focusing on HBEC and circulating white blood cells; and 4) Determination of the effects of Stx-1 on HBEC that could lead to CNS dysfunction in HUS, including mechanisms of cytotoxicity, regulation of vasoactive factor production, and modulation of platelet adherence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF VASOACTIVE DRUGS ON PERFUSION IN SEPTIC SHOCK Principal Investigator & Institution: Murray, Patrick T.; Anesthesia and Critical Care; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): This Mentored Patient-Oriented Research Career Development Award application requests support (or a proposal which includes mentorship by an experienced investigator, multidisciplinary support from the Chairs and faculty of several Departments. formal training in an NIH-funded Clinical Research Training Program. and a research project dissecting the regional and systemic effects of traditional and novel vasoactive drugs in critically ill patients with septic shock. Sepsis. the systemic inflammatory response to infection. may lead to refractorv hypotension (septic shock) and multiple organ system failure (MOSF). Despite increased cardiac output and oxygen delivery, death often ensues from refractory hypotension or subsequent MOSF. Standard indicators of adequate tissue perfusion which are used to titrate therapy in hypovolemic or cardiogenic shock are unreliable in hyperdynamic septic shock. Rational septic shock therapy would preferably be guided by targeted interventions tc? optimize end-organ perfusion and function, and reverse detectable tissue hypoperfusion. The primary end-organ index of adequate perfusion used in current clinical practice is renal perfusion and function. The effects of vasoactive drug therapy on renal perfusion and function are reliably quantifiable with sophisticated existing technology. This application seeks to determine the regional circulatory effects of restoring vascular contractility with standard exogenous catecholamines and the novel use of exogenous vasopressin, alone or in combination, in septic humans, focusing on renal perfusion and function. We will also examine the systemic and regional effects of targeted vasodilator therapy with fenoldopam (a novel dopaminergic agonist) in septic humans, alone or in combination with the aforementioned vasoconstrictors. Specifically, we will address the hypotheses that: 1) Addition of inotropic support (b-

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adrenoceptor stimulation) to intravenous fluids alone, or in combination with pure vasopressor therapy (a-adrenoceptor stimulation), improves renal perfusion and function in patients with sepsis or septic shock. 2) Titration of vasopressor therapy to a mean arterial pressure above the lower renal autoregulation threshold improves renal perfusion in patients with vasopressor-dependent septic shock. 3) Vasopressin therapy restores septic vascular contractility, augments vasopressor-responsiveness, reverses hypotension. and improves systemic and renal perfusion in human subjects receiving standard therapy for sepsis or septic shock. 4) Septic renal vasoconstriction is reversed, and renal perfusion and function improved, by selective renal vasodilator therapy. The overall aim of these experiments is to develop rational pharmacologic regimens and strategies for hemodynamic support in septic shock. focusing on prevention and management of septic acute renal failure, as a surrogate endpoint to optimize systemic perfusion in hyperdynamic states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL CELL INJURY: QUANTIFYING ITS ROLE IN ISCHEMIC ACUTE RENAL FAILURE Principal Investigator & Institution: Molitoris, Bruce A.; Professor of Medicine and Chief,; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (Taken directly from the application) Ischemia/reperfusion injury (IRI) is a major contributor to the organ damage that results in acute renal failure, one of the major causes of morbidity and mortality in hospitalized patients in the United States. We propose endothelial cell injury during the initiation phase of ARF (anoxia resulting from decreased vascular perfusion of the organ) occurs and is compounded thereafter by continued hypoxia in the cortical medullary region of the kidney. This results in further endothelial cell injury mediating epithelial cell injury and worsening organ dysfunction. Many factors are known to be involved in ischemia/reperfusion injury, but considerable data point to an important role for endothelial cells, as agents of injury in the kidney as well as other organs. Furthermore there is evidence that actin cytoskeletal alterations, occurring during cellular ATP depletion, mediate many of the structural and functional changes known to occur in ischemic cells. However, documentation of endothelial damage in the kidney is lacking. Therefore, we propose to test our hypothesis using an experimental model of ischemia/reperfusion injury in the mouse, and to determine the extent of initial and subsequent ischemia-induced endothelial injury and endothelial actin alterations. We will exploit recent advances in gene therapy and imaging technologies to image endothelial cell dynamics in live animals whose endothelial cells have been labeled with green fluorescent protein (GFP). We will also use this system to investigate the effect of ischemia/reperfusion on the dynamics of renal microvascular blood flow. Finally we will isolate GFP labeled microvascular endothelial cells and study the effects of ATP depletion on the actin cytoskeleton, actin depolymerizing factor (ADF) and expression of ADF using an adenoviral system to express a GFP-ADF chimera in cultured endothelial cells and in in vivo studies. These studies will provide a better understanding of the clinically important phenomenon of ischemia/reperfusion injury, and provide new methods for testing potential therapeutic approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENDOTHELIAL GB3 SPECIES INVOLVED IN HUS PATHOGENESIS Principal Investigator & Institution: Newburg, David S.; Biochem & Molecular Pharmacol; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: (adapted from the application) Acute renal failure and central nervous system (CNS) injury are life-threatening complications of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (HUS/TTP). Survivors of HUS/TTP sometimes suffer irreversible damage. This application tests two hypotheses regarding the binding and toxicity of Shiga toxin (Stx) of enterohemorrhagic Escherichia coli (EHEC) to renal and cerebral endothelial cells, a critical process in HUS/TTP pathogenesis: (1) Metabolic regulation of globotriaosylceramide (Gb3) and galactosyl Gb3 (Gal Gb3), the glycolipid receptor(s) for Stx in endothelial cells, is central to HUS/TTP. (2) Binding to specific Gb3/GaI Gb3 molecular species is responsible for biological activity of Stx. Specific fatty acid moieties in the ceramide portions of Gb3/GaI Gb3 have been shown to influence Stx binding, and specific Gb3 species relate more strongly than total Gb3 to Stx-induced injury of endothelial cells from human saphenous veins. Using the cells most relevant to HUS/TTP, human glomerular endothelial cells (hGEC) and human cerebral endothelial cells (hCEC), investigations will (1) Isolate and measure individual Gb3/GaI Gb3 species in hGEC and hCEC cultures incubated with and without TNF-alpha and IL1-beta. (2) Determine which Gb3 and Gal Gb3 species relate to Stx1 and Stx2 toxicity in cytotoxin-stimulated and unstimulated cultures and to Stx binding to cells. (3) Define the metabolic pathways that synthesize the individual molecular species of Gb3/GaI Gb3 in response to TNF-alpha or IL1-beta stimulation by selectively inhibiting previously described pathways. Determine which UDPgalactose: lactosylceramide alpha1, 4 galactosyltransferase isozymes control this synthesis. Elucidation of the different sensitivities of renal and cerebral cells to Stx may explain differences in the pathogenesis of renal and CNS disease in HUS/TTP. The detailed description of the expression of these endothelial cell Stx receptors will potentially lead to development of precisely targeted therapies that can reduce Stx toxicity and these devastating effects of HUS/TTP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ETIOLOGY OF NEPHROPATHY AND HYPERTENSION IN AASK PATIENT Principal Investigator & Institution: Lipkowitz, Michael S.; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: (adapted from the application) We will study the etiology of hypertension and nephropathy in the majority of the 1094 African-American patients in the AfricanAmerican Study of Kidney Disease in Hypertension (AASK). The AASK study is an NIH sponsored clinical multicenter trial comparing the effect of two levels of blood pressure control and three antihypertensive regimens on progression of hypertensive nephropathy in African Americans. There is a disproportionate number of African Americans with hypertensive target organ damage, suggesting a genetic susceptibility in this population; paradoxically, few studies have been performed to evaluate such genetic predisposition to disease in this high risk population. The patients of the AASK study offer a unique opportunity to prospectively determine the genetic factors involved in hypertension and hypertensive target organ damage within a high risk and under-

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studied population. The proposed studies will immortalize white blood cells from patients to provide a renewable source of tissue and DNA from this unique study group, and follow two approaches in assessing the etiology of hypertension, nephropathy, and their sequelae: 1. Studies are proposed to determine whether polymorphisms in candidate genes for hypertension, renal failure, and cardiac disease, including renin-angiotensin system genes, insulin resistance (beta3-adrenergic receptor and lipoprotein lipase) genes, Liddle's syndrome (beta and gammaENaC) genes, and others are related to hypertension or renal failure, severity/rate of progression of renal disease, severity/refractoriness of hypertension, electrocardiographic left ventricular hypertrophy, cardiovascular morbidity and mortality, and overall morbidity and mortality. 2. Additional studies will employ a new technique, mapping by admixture linkage disequilibrium (MALD), which uses the linkage disequilibrium caused by recent admixture of founder populations to localize genes linked to a particular phenotype within a 5-20 centiMorgan region in a genome-wide screen. By utilizing microsatellite markers from the carefully phenotyped patients of the AASK Study it should be possible to identify regions of interest containing genes associated with hypertension, renal failure, and the outcomes described above for candidate genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FETAL ORIGINS OF ADULT HYPERTENSION IN MICROSWINE Principal Investigator & Institution: Bagby, Susan P.; Professor of Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: A growing body of human epidemiologic evidence links intrauterine growth retardation (IUGR) and adult "Syndrome X": hypertension, obesity, diabetes, coronary artherosclerosis, and risk of renal failure. In preliminary studies in microswine, maternal isocaloric protein restriction (0.5% vs. 14%) during nephrogenesis (last 1/3 gestation +3 weeks post- natally) yields IUGR at 3 weeks, rapid catch-up growth to 123% of control body weight (overweight), adult hypertension, reduced nephron number by histology, and normal GFR suggesting single-nephron hyperfiltration. Renal cortical AT1 and AT2 receptors by quantitative autoradiography are abnormal in both 3week and 6-month old offspring of low-protein sows but in unique ways. We hypothesize that excess appetite/body image size generate excess protein load for the low number of nephrons, driving sustained intrarenal renin/AngII (RAS) activation to achieve nitrogen balance via single-nephron hyperfiltration. This RAS response is predicted to amplify the Na retention and extracellular fluid volume (ECV) excess expected with fewer nephrons, yielding hypertension. In a microswine model of maternal protein restriction/IUGR, studies in offspring will address: 1) whether IUGR modifies the activation state of circulating vs. intrarenal RAS at key developmental stages (preterm; 2-weeks postnatal; 3-month pre- hypertensive juvenile; and 6-month adult), including mRNA, protein, and activity levels for renin, angiotensinogen, ACE, AngII, and AT1/AT2 receptors at Low-Protein vs. Normal-protein offspring on ad lib normal diet; 2) whether IUGR enhances postnatal homeostatic responses of blood pressure (BP), ECV, Na balance, and circulating vs. intrarenal RAS components in vivo to dietary sodium manipulation to AngII blockade; 3) whether IUGR amplifies AT1 signaling efficacy in vitro in cultured vascular smooth muscle at each developmental stage; and 4) whether global caloric restriction to limit adult bodyweight to 75% of Normal-protein controls in IUGR offspring attenuates adult BP, body fat mass, ECV, and intrarenal RAS components. Results are relevant to etiologic mechanisms of

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hypertension and to the preventive management of IUGR-exposed children at risk for adult cardiovascular and renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: G PROTEIN REGULATION OF GLOMERULAR EPITHELIAL CELLS Principal Investigator & Institution: Denker, Bradley M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): The podocyte is a highly specialized epithelial cell that forms multiple foot processes along the glomerular capillary basement membrane. The "junction" between foot processes (slit diaphragm) is critical to selective glomerular permeability. Podocyte injury is a hallmark of glomerular disease and is prominent early in the course of diabetic nephropathy and other causes of chronic kidney disease. Loss of slit diaphragms results in altered glomerular hemodynamics, proteinuria and progressive renal failure. The slit diaphragm shares many features of typical epithelial cell junctions, yet little is known about how these structures are regulated. Based upon our work in MDCK cells, we hypothesize that G proteins are likely to be critical molecules for regulating slit diaphragm structure/function. Ga12 through interactions with ZO-1 is likely to regulate Rho and/or Src pathways and the actin cytoskeleton in podocytes. In Aim 1, the interaction of ZO-1 and Ga12 will be studied in mouse glomeruli and cultured podocytes by confocal and immunoelectron microscopy and by coprecipitations (immuno- and GST fusion proteins). Cultured podocytes will be used to define signaling from Ga12 to Rho and/or Src kinase pathways. A combination of inhibitors and stable podocyte cell lines expressing active and inactive mutants of Ga12, Rho, and Src will be established to characterize functional effects on the barrier (paracellular flux assays) and changes in structure (by confocal localization of signaling (Ga12, Rho, Src) and slit diaphragm (ZO-t, actin, nephrin)) proteins. In Aim 2, animal models will be developed to characterize these signaling pathways in-vivo. Two approaches will be utilized; A "knock in" of active Ga12 (Q229L) and transgenic podocyte specific expression of Q229La12. A targeting construct for the "knock in" is nearly complete, and the mouse podocin (NPHS2) promoter wil be used for targeting activated Ga12 to the podocyte. Animals will be studied biochemically for evidence of renal disease (proteinuria, creatinine) and morphologically by light and electron microscopy at various ages. Results from studies in cultured podocytes will determine future transgenic models (Rho, Src). These studies will reveal novel insights into regulation of podocyte structure and function. The animal models will extend these findings to in-vivo systems where novel treatment strategies for common podocyte diseases (diabetes and others) can be tested. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE DISCOVERY IN HERITABLE RENAL HYPODYSPLASIA Principal Investigator & Institution: Lozanoff, Scott; Anatomy & Reproductive Biology; University of Hawaii at Manoa Honolulu, Hi 96822 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Renal hypodysplasia (RHD) is a congenital disease that results in abnormally small and dysplastic kidneys. RHD is associated with chronic renal failure since the excretory portion does not differentiate properly and renal tubules progressively distend due to decreased filtration efficiency. Genes directing dysmorphogenetic events in RHD remain obscure. This project utilizes a radiation

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induced mutation in the 3H1 mouse called Brachyrrhine (Br) that inherits RHD as an autosomal semidominant trait. The overall goal of this project is to determine the genetic basis of RHD using Br as a model. Previously, Br was mapped to the distal portion of murine chromosome 17 (chr17). The first specific aim of this project is to undertake a high resolutioin microsatellite linkage analysis of distal chrl 7 to isolate a 100 - 500 kilobase region utilizing a large back cross mouse DNA sample followed by an in silico analysis of the candidate gene region using Celera and Sanger Gene Discovery databases. The second aim is to screen renal tissues of mutant and normal embyos at gestational days 13 and 14 for candidate gene expression using Northern blot analysis. It is expected that a gene deletion will be identified since the mutant phenotype and inheritance pattern is consistent with a radiation induced doubled stranded break and segment deletion. If a deletion is indicated, renal mRNA expression patterns in the mutant will be compared to corresponding normal renal tissue using RT-PCR and in situ hybridization, while associated protein analysis will utilize immunohistochemical methods. Specific aim 3 will sequence each exon in the candidate region using 3H1+/'+ and Br/Br DNA samples. Thus, the mutation in 3H1 Br will be determined even if a deletion is not found in Specific Aim 2. Additional methods will be utilized including SSCP and heteroduplex analysis to identify mutations in exons that may have been missed. As a result of this project, the gene responsible for RHD in 3H1 Br/Br mice will be identified. This sequence will be subjected to a mouse-human homology search and it is likely that a corresponding human gene will be identified since distal murine chr17 shares a high degree of sequence affinity with human chr 2p21.1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC /ENVIRONMENTAL INFLUENCES ON SLE NEPHRITIS Principal Investigator & Institution: Gilkeson, Gary S.; Professor; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies and immune complex mediated glomerulonephritis. African- Americans have a three-fold increased incidence of SLE, more frequently develop nephritis, more frequently progress to renal failure and have increased mortality compared to whites. The worse prognosis in African-Americans may represent a generalized predisposition towards renal failure following any renal injury rather than being lupus specific. Environmental exposures such as smoking and exposure to occupational or environmental agents (i.e., lead, mercury, silica) may affect the development and progression of lupus nephritis. Our central hypothesis is that there are specific genetic factors that interact with environmental exposures leading to progressive renal disease in African-Americans with lupus. The Carolina Lupus Study includes 265 SLE patients who were diagnosed between January 1, 1995 and July 31, 1999. This cohort of patients provides an opportunity to examine renal disease and its progression in African- American SLE patients matched with appropriate population based controls. The Gullah population lives on the sea islands of South Carolina. They are unique in their genetic homogeneity with minimal Caucasian admixture (